A selenium-based ionic liquid as a recyclable solvent for the catalyst-free synthesis of 3-selenylindoles

Article abstract of DOI:10.3390/molecules18044081

The ionic liquid 1-butyl-3-methylimidazolium methylselenite, [bmim][SeO₂(OCH₃)], was successfully used as solvent in the catalyst-free preparation of 3-arylselenylindoles by the reaction of indole with ArSeCl at room temperature. The products were obtained selectively in good yields without the need of any additive and the solvent was easily reused for several cycles with good results.

Full text of DOI:10.3390/molecules18044081

Molecules 2013, 18, 4081-4090; doi:10.3390/molecules18044081
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Selenium-Based Ionic Liquid as a Recyclable Solvent for the
Catalyst-Free Synthesis of 3-Selenylindoles
Everton G. Zimmermann 1, Samuel Thurow 1, Camilo S. Freitas 1, Samuel R. Mendes 2,
Gelson Perin 1,*, Diego Alves 1, Raquel G. Jacob 1 and Eder J. Lenardão 1,*
1
LASOL – CCQFA, Universidade Federal de Pelotas — UFPel, P.O. Box 354, 96010-900, Pelotas,
RS, Brazil
2
GAPAM, Departamento de Química, Universidade do Estado de Santa Catarina, 89219-719,
Joinville, SC, Brazil
* Authors to whom correspondence should be addressed; E-Mails: gelson_perin@ufpel.edu.br (G.P.);
lenardao@ufpel.edu.br (E.J.L.). Tel.: +55-53-3275-7357 (E.J.L.); Fax: +55-53-3275-7533 (E.J.L.).
Received: 18 February 2013; in revised form: 28 March 2013 / Accepted: 2 April 2013 /
Published: 5 April 2013
Abstract: The ionic liquid 1-butyl-3-methylimidazolium methylselenite, [bmim][SeO2(OCH3)],
was successfully used as solvent in the catalyst-free preparation of 3-arylselenylindoles by
the reaction of indole with ArSeCl at room temperature. The products were obtained
selectively in good yields without the need of any additive and the solvent was easily
reused for several cycles with good results.
Keywords: selenium ionic liquid; selenium compounds; arylselenylindoles; indoles
1. Introduction
Functionalized indoles, such as 3-arylthioindoles have attracted the attention of researchers in
organic synthesis and medicinal chemistry due their potent pharmacological activities, including the
inhibition of breast cancer cells [1] and of 5-lipoxygenase, which may increase the antitumor activity
of the drug celecoxib [2], and in the treatment of heart disease [3] and HIV [4]. In this sense, there are
a range of methods to synthesize this class of compounds, most of them starting from indoles and an
electrophilic sulfur reagent [5–8].
Despite the fact that the usefulness of organoselenium compounds in chemical sciences has already
been described in a great number of reviews and books [9–15] the synthesis of 3-arylselenylindoles

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and their potential bioactivity have not been extensively studied. These compounds can be obtained by
electrophilic cyclization of 2-alkynylanilines with arylselenyl chlorides [16,17] or iodides [18], by the
annulation of 2-(gem-dibromo(chloro)vinyl)-N-methylsulfonylanilines with diselenides [19] or by the
cyclization of 2-styrylacetanilides using N-phenylselenosuccinimide [20].
The direct selenylation of the easily available indole core, which is a more direct route to
3-arylselenylindoles, was even less explored, as for example in the indoline dehydrogenation using
phenylseleninic anhydride, (PhSeO)2O [21–23] or phenylseleninic acid, PhSeOH [24] (in these works
3-phenylselenylindole was a side product) and in the reaction of 2-acylphenylselenocyanates with
phenylhydrazine (only one example) [25]. The reactions between indoles and electropilic selenium
species catalyzed by I2/FeF3 [26] and p-TsOH [27] were also described. More recently, Silveira and
co-workers [28] used the PhSeSePh/TCCA/MgO system to generate PhSeCl in situ, which was reacted
with several indoles to give the respective 3-arylselenylindoles in good yields.
The use of ionic liquids (ILs) as solvent and/or catalyst has attracted much attention in the last
years. Because product isolation or catalyst recycling in ILs is very easy and, in some cases, rate
accelerations and/or selectivity improvements are also observed, they are regarded as environmentally
friendly, green solvents [29–33]. In this context, the use of the new selenium-based ILs phenylbutyl-
ethyl selenonium tetrafluoroborate, [pbeSe][BF4] and 1-butyl-3-methylimidazolium methylselenite,
[bmim][SeO2(OCH3)] (Figure 1) was recently reported. The selenonium IL was used as an efficient
catalyst in several acid-catalyzed reactions [34–36], while the selenite IL was employed in the
oxidative carbonylation of aniline [37], the base-free oxidation of thiols to disulfides [38] and in the
synthesis of vinyl sulfides [39].
Figure 1. Structures of the selenium-based ionic liquids.
N
N
Se
O
O
BF4
Se OCH3
[pbeSe][BF4]
[bmim][SeO2(OCH3)]
To the best of our knowledge, the preparation of 3-arylselenylindoles directly from indoles and
electrophilic selenium species under acid-free conditions was not described. In this context, and due
our ongoing interest in new applications for selenium-based ionic liquids and selenium-containing
compounds, we decide to investigate the use of [bmim][SeO2(OCH3)] as solvent for the general, catalyst-
free arylselenation of indoles to prepare 3-arylselenylindoles (Scheme 1).
2. Results and Discussion
Our initial efforts were made towards the determination of the optimum conditions to perform the
reaction. Thus, we chose indole (1a) and phenylselenyl chloride (2a) to establish the best conditions
for the arylselenylation reaction (Table 1).

Molecules 2013, 18
Scheme 1. Synthesis of 3-arylselenylindoles using [bimim][SeO2(OCH3)] as solvent.
4083
Se
R2
R
Se
[bmim][SeO2(OCH3)]
N2, r.t.
R
Cl
+
N
R2
R1
N
1a-c
2a-c
R1
3a-i
We examined the effect of temperature, use of nitrogen atmosphere and different ionic liquids, such
as [bmin][PF6], [bmin][BF4], [bmim][SeO2(OCH3)] and [pbeSe][BF4]. Except for [bmim][PF6] (Table 1,
entry 3), the desired selenylated indole 3a was isolated in all the tested conditions and the best yields
were observed using [bmim][SeO2(OCH3)] as solvent (78 and 79% yields, entries 1 and 6). In contrast,
the selenonium ionic liquid [pbeSe][BF4] was not stable under the reaction conditions, affording a
lower yield of 3a among a mixture of diorganyl selenides resulting from the IL (Table 1, entry 2). We
also verified the influence of the electrophilic selenium species in the reaction. It was found that when
PhSeBr was used the yield decreased to 57% (Table 1, entry 5), while N-phenylselenyl phthalimide
(PSP) afforded 3-phenylselenylindole 3a in a similar yield to PhSeCl (79%, entry 6). Since PhSeCl is
cheaper than PSP, it is advantageous to use the former reagent instead PSP. It was also observed that
when an open atmosphere is used or the mixture is heated, the yield of 3a decreases. In the second
case, decomposition of the IL was observed, with darkening of the solution. Thus, the best reaction
conditions were defined as stirring a solution of indole 3a (1.0 mmol) and phenylselenyl chloride 2a
(1.0 mmol) in [bmim][SeO2(OCH3)] (1.5 mL) at room temperature under a N2 atmosphere for 3 hours.
Table 1. Optimization studies for preparation of 3-(phenylselenyl)-1H-indole a.
Se
Se
ionic liquid
X
+
conditions
N
N
H
H
2
1a
3a
entry
ionic liquid
X
Cl
Cl
Cl
Cl
Br
time (h) yield (%) b
1
2
3
4
5
[bmim][SeO2(OCH3)]
[pbeSe][BF4]
3
3
78
39c
NRd
28
[bmim][PF6]
24
3
[bmim][BF4]
[bmim][SeO2(OCH3)]
3
57
6
[bmim][SeO2(OCH3)]
3
79
a
The reaction was performed using indole (1a, 1.0 mmol) and electrophilic selenium species
b
(1.0 mmol) in ionic liquid (1.5 mL) at room temperature and under a N2 atmosphere. Isolated
yields. c Decomposition of the IL was observed. d No reaction.
With these optimized conditions in hands, a detailed study was performed with different indoles and
arylselenyl chlorides, showing the generality of the method (Table 2).

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Table 2. Synthesis of 3-organylselanylindoles a.
Se
R2
R
Se
[bmin][SeO2(OCH3)]
R
Cl
+
N2, r.t.
N
R2
R1
N
1a-c
2a-c
R1
3a-i
Yield (%)
Entry
Indole 1a–c
2a–c
Product 3a–i
Time (h)
b
Se
Se
Cl
1
3
78 (74)c
73
N
H
2a
N
1a
3a
H
Se
Se
Cl
2
2
N
H
2b
N
1a
3b
H
Se
Cl
Se
Cl
N
H
3
4
5
3
3
2
55
68
65
Cl
2c
N
1a
3c
H
Se
Se
Cl
N
2a
N
1b
3d
Se
Se
Cl
N
2b
1b
N
3e
Se
Cl
Se
Cl
N
6
3
3
53
74
Cl
2c
1b
N
3f
Se
Br
Se
Br
Cl
N
H
7
8
2a
N
1c
3g
H
Br
Se
Se
Br
Cl
N
H
2
3
65
62
2b
N
1c
3h
H
Br
Se
Cl
Se
Br
Cl
N
H
9
Cl
2c
N
1c
3i
H
a
The reaction was performed using indole (1, 1.0 mmol) and electrophilic selenium species (2,
1.0 mmol) in ionic liquid (1.5 mL) at room temperature and under N2 atmosphere. b Isolated yields.
c Reaction performed in a 10 mmol scale and using 6 mL of IL.

Molecules 2013, 18
4085
From the results listed in Table 2, it can be seen that [bmim][SeO2(OCH3)] was a good reaction
medium to afford a wide range of 3-arylselenylindoles. A possible role of the IL here could be a
neutralizing effect in the HCl released in the reaction.
The presence of electron-donor and electron-withdrawing groups on the selenium species did
not affect substantially the yields or the reaction time. Thus, indole (1a) reacted with
p-tolylselenyl chloride (2b) under our conditions to afford 3-p-tolylselenylindole (3b) in 73% yield
after 3 h (Table 2, entry 2). Analogously, 4-chlorophenylselenyl chloride (2c) afforded the respective
3-arylselenylindole (3c) in 55% yield after 3 h after reaction with 1a (entry 3). We also extended our
protocol to N-methyl-1H-indole (1b), which afforded the 3-arylselenylindoles 3d–f after reaction with
2a–c in slightly lower yields than those obtained for the parent compound 3a (Table 2, entries 4–6).
Similarly, the functionalized 5-bromo-1H-indole (3c) reacted at room temperature with the arylselenyl
chlorides 2a–c in presence of [bmim][SeO2(OCH3)] to selectively afford the desired 5-bromo-3-
(arylselanyl)-1H-indoles 3g–i in good yields after short reaction times (Table 2, entries 7–9).
Additionally, a reuse study of the ionic liquid was carried out for the reaction of 1a with 2a to
obtain 3a. After stirring at r.t. during 3 h, the reaction mixture was diluted with ether (3  5.0 mL). The
upper organic phase was washed with water, the solvent evaporated and the product was isolated. The
remaining [bmim][SeO2(OCH3)] was directly reused for further reactions, simple by adding more
reagents 1a and 2a. It was observed that as the IL was being reused, it gradually darkened, from an
initial light yellow to orange and then to red and finally brown, which may be indicative of its
decomposition. It was observed that a good level of efficiency was maintained up until the fourth cycle
and it dropped in the fifth and sixth cycles (Table 3).
Table 3. Reuse of [bmim][SeO2(OCH3)].
Se
Se
[bmim][SeO2(OCH3)]
Cl
+
N2, r.t.
N
H
N
2a
1a
3a
H
Cycle
Time (h)
Yield of 3a (%) a
1
2
3
4
5
6
4
4
77
73
4
75
4
70
24
16
24
trace
a Yields are given for isolated products.
3. Experimental
3.1. General
Nuclear magnetic resonance spectra (1H- and 13C-NMR) were obtained at 200 and 400 MHz on
Bruker DPX spectrometers. Spectra were recorded in CDCl3 solutions. Chemical shifts are reported in
ppm, referenced to tetramethylsilane (TMS) as the external reference. Data are reported as follows:

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chemical shift (δ), multiplicity, coupling constant (J) in Hertz and integrated intensity. Carbon-13
nuclear magnetic resonance spectra (13C-NMR) were obtained at 50 and 100 MHz on Bruker DPX
spectrometers. Spectra were recorded in CDCl3 solutions. Chemical shifts are reported in ppm, referenced
to the solvent peak of CDCl3. Mass spectra (MS) were measured on a Shimadzu GCMS-QP2010 mass
spectrometer. Column chromatography was performed using Merck Silica Gel (230–400 mesh). Thin
layer chromatography (TLC) was performed using Merck Silica Gel GF254, 0.25 mm thickness. For
visualization, TLC plates were either placed under ultraviolet light, or stained with iodine vapor, or
acidic vanillin. All solvents were used as purchased unless otherwise noted. p-Tolylselenyl chloride
(2b) and 4-chlorophenylselenyl chloride (2c) [40] and the ionic liquids [bmim][SeO2(CH3)] [37] and
[pbeSe][BF4] [34] were synthesized as described in the literature.
3.2. General Synthesis Procedure
To a mixture of indole 1 (1.0 mmol) in [bmim][SeO2(OCH3)] (1.5 mL) under a N2 atmosphere,
organylselenyl chloride 2 (1.0 mmol) was added at room temperature and the mixture was stirred for
the time indicated in Table 2. The progress of the reaction was monitored by TLC. After the reaction
was complete, the product was extracted by successive washings with ether (3 × 5 mL). The upper
organic phase was washed with water, dried over MgSO4, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent. All the
compounds were characterized and the corresponding spectral data are listed below:
1
3-(Phenylselenyl)-1H-indole (3a) [26]: Yield: 0.213 g (78%). H-NMR (CDCl3, 400 MHz): δ = 8.35
(br s, 1H), 7.64 (d, J = 7.9, 1H), 7.39–7.43 (m, 2H), 7.22–7.25 (m, 4H), 7.08–7.14 (m, 3H). 13C-NMR
(100 MHz, CDCl3): δ = 136.4, 133.8, 131.2, 129.9, 128.9, 128.7, 125.6, 122.9, 120.8, 120.3, 111.3,
98.2. MS: m/z (rel. int.) 273 (6.0), 193 (100.0), 117 (5.3), 77 (21.0).
1
3-(p-Tolylselenyl)-1H-indole (3b): Yield: 0.210 g (73%). H-NMR (CDCl3, 200 MHz): δ = 8.18 (s,
1H), 7.63 (d, J = 7.6, 1H), 7.14–7.32 (m, 7H), 6.91 (d, J = 7.6, 1H), 2.20 (s, 3H). 13C-NMR (50 MHz,
CDCl3): δ = 136.5, 135.6, 133.4, 130.8, 130.5, 129.7, 129.4, 122.8, 120.8, 120.4, 111.3, 99.0, 20.8.
MS: m/z (rel. int.) 287 (2.7), 207 (100.0), 117 (4.9), 77 (14.4).
3-(4-Chlorophenylselenyl)-1H-indole (3c): Yield: 0.169 g (55%). 1H-NMR (CDCl3, 200 MHz): δ = 8.39
(br s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.38–7.42 (m, 2H), 7.03-7.29 (m, 6H). 13C-NMR (50 MHz,
CDCl3): δ = 136.6, 132.1, 131.8, 130.3, 129.9, 129.0, 123.2, 121.1, 120.3, 111.4, 98.4. MS: m/z (rel.
int.) 307 (4.9), 227 (100.0), 116 (12.5), 77 (14.1).
1
1-Methyl-3-(phenylselenyl)-1H-indole (3d) [27]: Yield: 0.195 g (68%). H-NMR (CDCl3, 200 MHz):
δ= 7.63 (d, J = 7.8, 1H), 7.07–7.35 (m, 9H), 3.74–3,80 (s, 3H). 13C-NMR (50 MHz, CDCl3): δ = 137.6,
135.5, 134.2, 130.8, 129.3, 128.9, 125.6, 122.4, 120.5, 120.4, 109.5, 96.4, 33.0. MS: m/z (rel. int.) 287
(8.0), 207 (100.0), 130 (18.7), 77 (11.2).
1-Methyl-3-(p-tolylselenyl)-1H-indole (3e): Yield: 0.196 g (65%). 1H-NMR (CDCl3, 200 MHz): δ = 7,61
(d, J = 7.9, 1H), 7.35–6.87 (m, 8H), 3.79 (s, 3H), 2.22 (s, 3H). 13C-NMR (50 MHz, CDCl3): δ = 137.6,

Molecules 2013, 18
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135.4, 135.2, 130.8, 130.2, 129.7, 129.3, 122.4, 120.6, 120.3, 109.4, 97.0, 32.8, 20.8. MS: m/z (rel.
int.) 301 (5.4), 221 (100.0), 130 (17.1).
1
3-(4-Chlorophenylselenyl)-1-methyl-1H-indole (3f): Yield: 0.170 g (53%). H-NMR (CDCl3, 200
MHz): δ = 7.59 (d, J = 7.7, 1H), 7.03–7.39 (m, 8H), 3.83 (s, 3H). 13C-NMR (50 MHz, CDCl3):
δ = 137.5, 135.6, 132.5, 131.5, 130.4, 129.9, 128.9, 122.6, 120.5, 120.3, 109.6, 91,7, 33.0. MS: m/z
(rel. int.) 321 (8.7), 241 (100.0), 130.0 (26.7), 77 (11.5).
1
5-Bromo-3-(phenylselenyl)-1H-indole (3g) [26]: Yield: 0.260 g (74%). H-NMR (CDCl3, 400 MHz):
δ= 8.38 (br s, 1H), 7.74 (s, 1H), 7.38 (d, J = 2.2, 1H), 7.09–7.33 (m, 8H). 13C-NMR (100 MHz,
CDCl3): δ = 135.0, 133.3, 132.4, 131.8, 129.0, 128.7, 125.9, 125.8, 122.9, 114.3, 112.9, 97.8. MS: m/z
(rel. int.) 351 (15.2), 271 (100.0), 192 (73.8), 116 (11.3), 77 (42.3).
1
5-Bromo-3-(p-tolylselenyl)-1H-indole (3h) [28]: Yield: 0.237 g (65%). H-NMR (CDCl3, 200 MHz):
δ = 8.42 (br s, 1H), 7.77 (s, 1H), 7.42 (d, J = 2.3, 1H), 7.12–7.30 (m, 4H), 6.95 (d, J = 8.0, 2H), 2.36 (s,
13
3H). C-NMR (50 MHz, CDCl3): δ = 135.8, 135.0, 132.1, 131.8, 129.9, 129.3, 129.2, 125.8, 122.9,
114.3, 112.8, 98.4, 20.9. MS: m/z (rel. int.) 365 (18.3), 285 (100.0), 194 (12.7), 91 (42.2).
1
5-Bromo-3-(4-chlorophenylselenyl)-1H-indole (3i): Yield: 0.239 g (62%). H-NMR (CDCl3, 400 MHz):
δ = 8.47 (br s, 1H), 7.71 (d, J = 1.7, 1H), 7.41 (d, J = 2.5, 1H), 7.25–7.33 (m, 2H), 7.06–7.12 (m, 4H).
13C-NMR (100 MHz, CDCl3): δ = 135.0, 132.4, 131.8, 131.6, 131.5, 130.0, 129.1, 126.0, 122.7, 114.4,
114.4, 112.9. MS: m/z (rel. int.) 385 (5.6), 307 (75.0), 191 (72.1), 115 (46.8), 75 (100.0).
4. Conclusions
In summary, we present here the first report on the use of the ionic liquid [bmim][SeO2(OCH3)] in
the selective synthesis of 3-arylselenylindoles. The products were obtained in good yields at room
temperature in a relatively short time without the need of any additive. Moreover, the IL could be
reused directly for up to four cycles with good performance.
Acknowledgments
The authors are grateful to FAPERGS and CNPq (PRONEX 10/0005-1, PRONEM 11/2026-4, PqG
11/0719-3 and PqG 11/0881-2), CAPES and FINEP for their financial support.
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Sample Availability: Samples of the compounds 3a–i are available from the authors.
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